The overall goal of this proposal is to determine whether hepatitis C virus (HCV) infection alters bone metabolism and leads to bone fragility. Multiple epidemiologic studies have shown that HCV infection is associated with a several fold increased risk of fracture, both in those with HCV monoinfection and HIV/HCV coinfection. However, it is unclear whether this increased fracture risk is due to HCV infection itself, behavioral factors associated with HCV infection, or the consequences of chronic liver disease. Another major limitation of previous studies is that conventional bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) has been the primary outcome measure. However, BMD by DXA only explains about 50% of fracture risk. Newer modalities, such as quantitative computed tomography (QCT) and reference point indentation can provide additional information about bone health beyond conventional DXA by measuring differences bone strength and bone quality. By using two separate NIH-funded studies as a platform, this project leverages the strength of clinical HCV research at Johns Hopkins and proposes complementary approaches to answer the question of whether HCV infection itself impacts bone health. The following aims are proposed: 1) To determine whether successful HCV treatment with direct-acting antivirals (DAA) leads to changes in bone turnover and improved BMD in HIV/HCV coinfected (Aim 1A) and HCV monoinfected patients (Aim 1B), 2) To determine the effect of chronic HCV infection on measures of bone density, strength, and quality using state of the art imaging methodologies and to assess the added effect of treated and untreated HIV infection on bone outcomes. Highly effective, oral treatments which can cure HCV in the majority of patients have recently become available, but the cost of treatment is high. A finding that HCV infection impacts bone turnover, density, and strength would provide a compelling basis for expanding treatment guidelines beyond liver fibrosis and include osteoporosis as an extra-hepatic manifestation of HCV for which treatment should be considered. In addition, these studies will determine which aspects of bone are most affected by chronic HCV infection and how HIV and its treatment may add to fracture risk in HIV/HCV co- infection. In this way, the pathogenesis of bone disease in HIV and HCV will be better understood and future prevention and treatment strategies will be better informed.